Ribonucleotide reductase

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DNA regulation, replication and repair are processes fundamental to all known organisms and the sliding clamp proliferating cell nuclear antigen (PCNA) is central to all these processes. S-phase delaying protein 1 (Spd1) from S. pombe, an intrinsically disordered protein that causes checkpoint activation by inhibiting the enzyme ribonucleotide reductase, has one of the most divergent PCNA binding motifs known. Using NMR spectroscopy, in vivo assays, X-ray crystallography, calorimetry, and Monte Carlo simulations, an additional PCNA binding motif in Spd1, a PIP-box, is revealed...

A growing body of literature reports on the combined use of peptide receptor radionuclide therapy (PRRT) with other anti-tumuor therapies in order to anticipate synergistic effects with perhaps increased safety issues. Combination treatments to enhance PRRT outcome are based on improved tumour perfusion, upregulation of somatostatin receptors (SSTR), radiosensitization with DNA damaging agents or targeted therapies. Several Phase 1 or 2 trials are currently recruiting patients in combined regimens. The combination of PRRT with cytotoxic chemotherapy, capecitabine and temozolomide (CAPTEM), seems to become clinically useful especially in pancreatic neuroendocrine tumours (pNETs) with acceptable safety profile...

In the postulated catalytic cycle of class Ib Mn2 ribonucleotide reductases (RNRs), a MnII 2 core is suggested to react with superoxide (O2 ·- ) to generate peroxido-MnII MnIII and oxo-MnIII MnIV entities prior to proton-coupled electron transfer (PCET) oxidation of tyrosine. There is limited experimental support for this mechanism. We demonstrate that [MnII 2 (BPMP)(OAc)2 ](ClO4 ) ( 1 , HBPMP = 2,6-bis[(bis(2 pyridylmethyl)amino)methyl]-4-methylphenol) was converted to peroxido-MnII MnIII ( 2 ) in the presence of superoxide anion that converted to (μ-O)(μ-OH)MnIII MnIV ( 3 ) via the addition of an H+ -donor ( p- TsOH) or (μ-O)2 MnIII MnIV ( 4 ) upon warming to room temperature...

During myogenesis and regeneration, the proliferation and differentiation of myoblasts play key regulatory roles and may be regulated by many genes. In this study, we analyzed the transcriptomic data of chicken primary myoblasts at different periods of proliferation and differentiation with protein‒protein interaction network, and the results indicated that there was an interaction between cyclin-dependent kinase 1 (CDK1) and ribonucleotide reductase regulatory subunit M2 (RRM2). Previous studies in mammals have a role for RRM2 in skeletal muscle development as well as cell growth, but the role of RRM2 in chicken is unclear...

Forty-six percent of the world's population resides in rural areas, the majority of whom belong to vulnerable groups. They mainly use cheap solid fuels for cooking and heating, which release a large amount of PM2.5 and cause adverse effects to human health. PM2.5 exhibits urban-rural differences in its health risk to the respiratory system. However, the majority of research on this issue has focused on respiratory diseases induced by atmospheric PM2.5 in urban areas, while rural areas have been ignored for a long time, especially the pathogenesis of respiratory diseases...

Cancer cells grown in 3D spheroid cultures are considered more predictive for clinical efficacy. The marine natural product dragmacidin D induces apoptosis in MDA-MB-231 and MDA-MB-468 triple-negative breast cancer (TNBC) spheroids within 24 h of treatment while showing no cytotoxicity against the same cells grown in monolayers and treated for 72 h. The IC50 for cytotoxicity based on caspase 3/7 cleavage in the spheroid assay was 8 ± 1 µM in MDA-MB-231 cells and 16 ± 0.6 µM in MDA-MB-468 cells at 24 h...

BACKGROUND: Atypical teratoid rhabdoid tumors (ATRT) is a rare but aggressive malignancy in the central nervous system, predominantly occurring in early childhood. Despite aggressive treatment, the prognosis of ATRT patients remains poor. RRM2, a subunit of ribonucleotide reductase, has been reported as a biomarker for aggressiveness and poor prognostic conditions in several cancers. However, little is known about the role of RRM2 in ATRT. Uncovering the role of RRM2 in ATRT will further promote the development of feasible strategies and effective drugs to treat ATRT...

One fundamental principle that underlies various cancer treatments, such as traditional chemotherapy and radiotherapy, involves the induction of catastrophic DNA damage, leading to the apoptosis of cancer cells. In our study, we conduct a comprehensive dose-response combination screening focused on inhibitors that target key kinases involved in the DNA damage response (DDR): ATR, ATM, and DNA-PK. This screening involves 87 anti-cancer agents, including six DDR inhibitors, and encompasses 62 different cell lines spanning 12 types of tumors, resulting in a total of 17,912 combination treatment experiments...

PURPOSE: Pancreatic cancer (PC) remains a lethal disease, and gemcitabine resistance is prevalent. However, the biomarkers suggestive of gemcitabine resistance remain unclear. METHODS: Bioinformatic tools identified ribonucleotide reductase catalytic subunit M1 (RRM1) in gemcitabine-related datasets. A cox regression model revealed the predictive value of RRM1 with clinical features. An external clinical cohort confirmed the prognostic value of RRM1. RRM1 expression was validated in gemcitabine-resistant cells in vitro and in orthotopic PC model...

Ribonucleotide reductase (RNR) catalyzes the reduction of ribonucleotides to deoxyribonucleotides in all organisms. There is an ∼35 Å long-range electron-hole transfer pathway during the catalytic process of class Ia RNR, which can be described as Tyr122 β ↔ [Trp48 β]? ↔ Tyr356 β ↔ Tyr731 α ↔ Tyr730 α ↔ Cys439 α. The formation of the Y122 • radical initiates this long-range radical transfer process. However, the generation mechanism of Y122 • is not yet clear due to confusion over the intermediate X structures...

UNLABELLED: Zinc is a vital transition metal for Streptococcus pneumoniae , but is deadly at high concentrations. Zn intoxication of S. pneumoniae results from a deficiency in Mn, which is required for key metabolic enzymes and defense against oxidative stress. Here, we report our identification and characterization of the function of the five homologous, CiaRH-regulated Ccn sRNAs in controlling S. pneumoniae virulence and metal homeostasis. We show that deletion of all five ccn genes ( ccnA , ccnB , ccnC , ccnD , and ccnE ) from S...

Candidatus Liberibacter spp is the most prevalent microorganism in the citrus plant, associated with Citrus Huanglongbing (HLB), which is transmitted by the psyllid vector. In Colombia, the vector Diaphorina citri Kugayama has been reported in different regions, but "Ca. Liberibacter asiaticus" (CLas) has only been detected in insect vectors, not in citrus host plants. To identify the presence and quantify the pathogen in citrus tissues, we employed a combined strategy that involved three techniques based on polymerase chain reaction (PCR)...

BACKGROUND: Prostate cancer is a leading cause of cancer-related deaths among men worldwide. Docetaxel chemotherapy has proven effective in improving overall survival in patients with castration-resistant prostate cancer (CRPC), but drug resistance remains a considerable clinical challenge. METHODS: We explored the role of Ribonucleotide reductase subunit M2 (RRM2), a gene associated with senescence, in the sensitivity of prostate cancer to docetaxel. We evaluated the RRM2 expression, docetaxel resistance, and ANXA1 expression in prostate cancer cell lines and tumour xenografts models...

The impact of N221S mutation in hRRM2B gene, which encodes the small subunit of human ribonucleotide reductase (RNR), on RNR activity and the pathogenesis of mitochondrial DNA depletion syndrome (MDDS) was investigated. Our results demonstrate that N221 mutations significantly reduce RNR activity, suggesting its role in the development of MDDS. We proposed an allosteric regulation pathway involving a chain of three phenylalanine residues on the αE helix of RNR small subunit β. This pathway connects the C-terminal loop of β2, transfers the activation signal from the large catalytic subunit α to β active site, and controls access of oxygen for radical generation...

Citrus greening disease was first reported in Saudi Arabia during the 1970's when characteristic foliar and fruit symptoms were observed in commercial citrus groves, however, "Candidatus Liberibacter asiaticus" (CLas) was not detected in symptomatic trees until 1981-1984 when CLas-like cells were observed by transmission electron microscopy in leaves collected from symptomatic citrus groves in southwestern Saudi Arabia. Despite the anticipated establishment of the CLas-Asian citrus psyllid (ACP) (Diaphorina citri Kuwayama) pathosystem, CLas presence has not been verified in suspect trees nor have ACP infestations been documented...

3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) has broad-spectrum antitumor activity. However, its role in osteosarcoma (OS) remains unclear. Therefore, this study explored the effects of 3-AP on OS in vitro and in vivo using three human OS cell lines (MG-63, U2-OS, and 143B) and a nude mice model generated by transplanting 143B cells. The cells and mice were treated with DMSO (control) or gradient concentrations of 3-AP. Then, various assays (e.g., cell counting kit-8, flow cytometry, immunohistochemistry, and western blotting) were performed to assess cell viability and apoptosis levels, as well as γH2A...

Visceral cestodiases, like echinococcoses and cysticercoses, are zoonoses of worldwide distribution and are responsible for public health problems in many countries, especially in underdeveloped regions. Current treatments have low efficiency and there are few drugs currently in use for chemotherapy, making the development of new anthelmintics an urgent matter. The nucleotide salvage pathways are the only ones available for nucleotide synthesis in cestodes and other parasitic helminths, and, here, we used in silico approaches to assess the potential of the enzymes in these pathways as targets for drug repurposing as anthelminthics...

Cancer is a genetic disease requiring multiple mutations for its development. However, many carcinogens are DNA-unreactive and nonmutagenic and consequently, described as nongenotoxic. One of such carcinogens is nickel, a global environmental pollutant abundantly emitted by burning of coal. We investigated activation of DNA damage responses by Ni and identified this metal as a replication stressor. Genotoxic stress markers indicated the accumulation of ssDNA and stalled replication forks, and Ni-treated cells were dependent on ATR for suppression of DNA damage and long-term survival...

OBJECTIVES: Cytotoxic nucleosides (gemcitabine, cytarabine…) are used for the treatment of various malignancies. Their activity is dependent on the interaction with several proteins and enzymes of nucleotide metabolism. It has for a long time been hypothesized that the clinical activity of nucleoside analogues can be predicted by studying corresponding genes or gene products in clinical samples. METHODS: In this short review, I will present old and new published data from our group and others about the prediction of activity of these drugs concentrating on gene-candidate approaches, and discuss biological and technical limitations of these...